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Medical Journal of Therapeutics Africa 2007 Vol 1, No 1
Page 61
HOW SICKLE CELL TRAIT PROTECTS AGAINST MALARIA
EC Pierce
University of the Sciences in Philadelphia,
600 South 43rd Street, Philadelphia, Pennsylvania, 19104-2744, USA.
Abstract
ing both HbA and HbS, protects against malaria.
PubMed was searched for research articles describing the sickle cell trait, defined as red blood cells
being heterozygous for normal hemoglobin (HbA)
and sickle cell hemoglobin (HbS). The search resulted in finding articles that supported the belief that
sickle cell trait protects against malaria in 1 population, 3 epidemiological, and 4 biochemical studies.
Pierce EC. How Sickle Cell Trait Protects
Against Malaria. Med J Therapeut Africa.
2007;1:61-62.
Keywords: malaria sickle cell anemia HbA HbS
sub-Saharan Africa
Methods
Introduction
Sickle cell anemia is an autosomal recessive genetic
disorder. In sickle cell anemia a single amino acid
substitution in HbA results in HbS, and red blood
cells are hard, sticky, and crescent-shaped. Sickle
red blood cells tend to stick together and block narrow blood vessels. Such blockages prevent oxygen
from reaching all parts of the body, causing tissue
damage, anemia, and painful episodes (crises) in a
patient's joints and bones.(1)
The goal of this report was to explain how the sickle cell trait, which results from red blood cells havChildren with Children with
HbA-HbS
HbA-HbA
Incidences of
mild clinical
malaria
Incidences of
hospitalization for
severe malaria
Incidences of
cerebral malaria
Incidences of
severe malarial
anemia
93
1195
6
191
1
34
1
48
Table 1. Children living on the coast of Kenya,
adapted from Ref 3.
After an initial internet search engine search on the
sickle cell trait and malaria, the PubMed database
was searched for the terms: "sickle cell anemia",
"sickle cell trait", "malaria", and "sickle cell trait protection".
Results
A total of 8 studies were found which gave evidence
of protection against malaria in humans with the
sickle cell trait, HbA-HbS. These were 1 population,
3 epidemiological, and 4 biochemical studies.
Williams and colleagues studied the effects of age
on malaria infection in children living on the coast of
Kenya and reported that children with HbA-HbS had
a 40% protective advantage against mild cases of
malaria. This protection increased with age from
20% to nearly 60% over the first 10 years of life.
After the age of 10, protection returned to around
30%.(2)
The effect of HbA-HbS on childhood diseases and
malaria was studied in over 3,000 children living on
the coast of Kenya. No significant effect of having
HbA-HbS on other childhood diseases was observed.
The study demonstrated that HbA-HbS protects
against malaria caused by Plasmodium falciparum,
(P falciparum) Table 1. The incidences of mild cases
of malaria (93 versus 1,195) and the incidences of
hospital admission for severe cases of malaria (6
versus 191) were significantly lower in children with
HbA-HbS. Parasite densities during both mild and
severe malaria episodes were significantly lower in
children with HbA-HbS. Children with HbA-HbS
admitted to the hospital for falciparum malaria had
a 4-fold lower parasitic density.(3)
Epidemiological studies in Nigeria measured the
number of P falciparum parasites in blood samples
of children with the sickle cell trait who had lowered
frequency of parasites and less malarial infections.
The report’s conclusions were that the lower frequency of parasites was mostly likely due to the
destruction of infected red blood cells.(4)
Aidoo and colleagues reported that children under 5
with HbA-HbS had fewer episodes of severe malaria
anemia (2 versus 4 crude incidence per 1,000 person-months). Because severe malarial anemia is a
major cause of death, a decreased number of
Sickle Cell Trait
Medical Journal of Therapeutics Africa 2007 Vol 1, No 1
episodes is evidence for the sickle cell trait protection against malaria-related deaths. Children with
HbA-HbS had reduced risks of high-density parasitemia (over 10,000 parasites.microL-1) (17.3 versus 20.0 crude incidence per 1,000 personmonths).(5)
In vitro studies by Roth and colleagues demonstrated that under conditions of both total and partial
deoxygenation, red blood cells infected with
Plasmodium falciparum sickled faster than noninfected red blood cells. Red blood cells infected with
ring forms of the Plasmodium parasites sickled nearly 8 times faster than non-infected cells. At every
oxygen saturation, red blood cells infected with
small parasites sickled more than non-infected red
blood cells.(6)
When a parasite invades a red blood cell, the parasite's metabolism reduces the oxygen in the cell. The
decrease in oxygen causes the red blood cell to sickle; those sickle cells, and the pathogens infecting
those cells, are then removed by the spleen or
destroyed by phagocytes. This clearance of infected
sickled red blood cells by the body's immune system
reduces and prevents malarial infections.(7)
Phagocytosis is enhanced in sickle cell trait red blood
cells infected with parasitic ring forms. These ring
forms are an early stage of development in the
malarial parasite's life cycle. The removal of these
early parasite forms is advantageous to the host
because the enhanced phagocytosis of these infected red blood cells reduces parasitic invasion and
growth. The parasitic ring forms are more rapidly
digested by monocytes than the more mature parasitic forms. The phagocytosis of more mature forms
of the parasite has been shown to affect the ability
of monocytes to repeat the phagocytic process.(8)
Malarial parasites cannot live in sickle cells because
the cell membrane of those distorted red blood cells
becomes porous. Nutrients that the parasite needs
to live escape through the permeable membrane of
the sickle red blood cells. Red blood cells of humans
with the sickle cell trait produce more superoxide
anion and hydrogen peroxide, which are toxic to
malarial parasites.(4)
Discussion
A benefit in having HbA-HbS to protect against
malaria was first suggested because of the high frequency of HbA-HbS in areas with high incidences of
malaria. The frequency of sickle cell disease is higher in Africa (16%) compared to the frequency in the
United States (4%), particularly in western Africa.(6)
Support for the concept that HbA-HbS is beneficial
came from research that concluded that humans
native to the highland regions of Africa did not have
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as high a frequency of the HbS gene as did humans
in the lowland regions.
Neither malaria, nor the gene for sickle hemoglobin
occurs in the cooler, drier climates of the African
highlands.(4)
Humans with normal hemoglobin have a greater risk
of dying from malaria.(6) The premature death of
individuals homozygous for HbA results in a lower
frequency of normal Hb genes within the population.
Humans with 2 sickle cell genes develop sickle cell
anemia, and also die at an early age. Heterozygous
humans are more likely to survive malarial infections
than humans homozygous for HbA. Carriers of the
genes for HbA-HbS are able to reproduce and pass
the sickle cell gene to their offspring. As a result,
HbA-HbS is sustained in the population at a relatively high frequency.(4)
Conclusion
The sickle cell trait, which results from having blood
heterozygous for HbA and HbS, protects against
malaria. Consequently, humans with the trait are
more likely to survive malarial infections and reproduce than humans homozygous for HbA or HbS. The
protective advantage also explains why the frequency of the sickle cell trait is higher in malaria-endemic areas found in sub-Saharan Africa.
References
1.Mayo Clinic Website. Sickle Cell Anemia: Introduction. At
www.mayoclinic.com. Accessed 14 Sep 2006.
2.Williams TN, Mwangi TW, Roberts DJ, Alexander ND,
Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. An
immune basis for malaria protection by the sickle cell trait.
PLoS Med. 2005;2(5):e128. Epub 2005 May 31.
3.Williams TN, Mwangi TW, Wambua S, Alexander ND,
Kortok M, Snow RW, Marsh K. Sickle cell trait and the risk of
Plasmodium falciparum malaria and other childhood diseases. J
Infect Dis. 2005;192:178-86. Epub 2005 May 31.
4.Information Center for Sickle Cell and Thalassemic Disorders.
Malaria and the Red Cell. At sickle.bwh.harvard.edu/malaria
_sickle.html. Accessed 16 Sep 2006.
5.Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile
FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V. Protective
effects of the sickle cell gene against malaria morbidity and
mortality. Lancet. 2002; 359:1311-2.
6.Roth EF Jr, Friedman M, Ueda Y, Tellez I, Trager W, Nagel
RL. Sickling rates of human AS red cells infected in vitro with
Plasmodium falciparum malaria. Science. 1978;202:650-2.
7.Friedman MJ. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci USA. 1978;75:1994-7.
8.Ayi K, Turrini F, Piga A, Arese P. Enhanced phagocytosis of
ring-parasitized mutant erythrocytes: a common mechanism that
may explain protection against falciparum malaria in sickle trait
and beta-thalassemia trait. Blood. 2004;104:3364-71.